The availability of 3-DMT-nucleoside synthons (eg amidites, phosphonates) will allow the chemical synthesis of unique oligonucleotide structures having important applications in the development of novel diagnostic and therapeutic agents and processes. In Phase I of this grant, synthesis methods for commercial scale preparation of 3'DMT-Nucleosides and their respective amidites and solid supports will be developed. Further, the synthetic capabilities of 3'DMT-synthons will be demonstrated by synthesis of normal and inversely linked oligonucleotides. In phase II, a prototype synthesis instrument accessing all eight amidite (eg 5'DMT and 3'DMT amidites) synthons will be developed allowing the automated synthesis of complex inversely linked oligonucleotides. The key design feature of the instrument will be a fluidics path which allows all eight amidites to have equivalently low dead volume resulting in economical consumption of the more expensive 3'DMT synthons. The instrument will be used to construct novel oligomers allowing investigation of their behavior in probing, priming, and hybridization studies.